Dendritic cells are efficient antigen presenting cells for the induction of immunity and in some cases, tolerance. However, mechanisms for antigen (Ag) uptake, processing, and presentation are not understood. Recent evidence reveals that DCs are rich in specialized intracellular vacuoles in which antigenic peptides gain excess to MHC molecules. Also, it has recently been shown that MIIVs or CIIVs of DCs express DEC-205, a receptor for adsorptive uptake and presentation. Molecular cloning showed DEC-205 to be a group VI C-type lectin with 10 carbohydrate recognition domains. DEC-205 may well be a receptor that DCs and thymic epithelium use to capture Ags and target endocytic vesicles for presentation. The aims are directed to elucidating the uptake and presentation mechanisms of DCs, with emphasis on the precise role of DEC-205 in endocytosis and targeting. This application proposes: 1) That DCs have an endocytic system specialized to internalize antigens and present these on MHC Class II. 2) That DEC-205 itself targets to intracellular vacuoles that lie beyond rapidly recycling early endosomes, particularly CIIVs. 3) That DCs can prevent particulate antigens on MHC class II and perhaps class I, as long as these are appropriately internalized and transported via antibodies to DEC-205. 4) That two separate regions in the cytoplasmic tail of DEC-205 mediate adsorptive uptake and presentation respectively. 5) That the cytoplasmic tail of DEC-205 will deliver ligands to antigen presenting late endosomes and thereby differ in function from the tails of other adsorptive endocytic receptors (the macrophage mannose receptor and low density lipoprotein receptor). 6) That the cell biological role of DEC-205 in epithelia and brain endothelium will be analogous to DCs, i.e., to target ligands away from terminal digestion in lysosomes and towards late endosomes utilized in transcytosis and/or peptide recycling.